Endothelial inflammation is critical in the initiation and progression of atherosclerosis and other cardiovascular diseases (CVDs). Tumor necrosis factor-α (TNF-α) is a pro-inflammatory cytokine that induces endothelial inflammation via activation of nuclear factor κB (NF-κB) signaling. Coiled-coil domain containing 3 (CCDC3) is a newly identified secretory protein mainly expressed in endothelial cells (ECs) and in adipose tissues. However, the function of CCDC3 in ECs is unclear. A published paper showed that TNF-α downregulates CCDC3 expression in ECs. We therefore investigated the role of CCDC3 in TNF-α-induced inflammatory response in ECs.
In response to inflammation, ECs express adhesion molecules including vascular cell adhesion molecule-1 (VCAM-1) that recruit leukocytes to the sites of infection or injury. In our study we found that stable overexpression of CCDC3 decreased, while stable knockdown of CCDC3 increased TNF-α-induced expression of VCAM-1 at the mRNA and protein levels in ECs. Mechanistically, stable overexpression of CCDC3 decreased TNF-α-induced p65 and p50 nuclear translocation and nuclear NF-κB activity, suggesting that CCDC3 attenuates TNF-α-induced gene expression by inhibiting NF-κB signaling in ECs. Importantly, we found that CCDC3 in the conditioned medium (CM) as well as the purified CCDC3 decreased TNF-α-induced expression of VCAM-1 in receiving ECs, suggesting that CCDC3 has a paracrine/autocrine function. Interestingly, CCDC3 in CM can enter the receiving ECs. Taken together, our work demonstrates that CCDC3 represses TNF-α/NF-κB-induced pro-inflammatory response in ECs, suggesting a potential anti-inflammatory and atheroprotective role of CCDC3 in vascular ECs.

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